What the eye doesn’t see?

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I saw someone with possible MS earlier this week and he had been told that he couldn’t have MS because he only had one detectable lesion on his MRI. Is this correct?



The problem: ‘MS has become an MRIscopic disease’.




The diagnosis of MS remains clinical and is underpinned by the need to show (1) dissemination in time (typically new activity 4 weeks apart or the presence of locally produced oligoclonal IgG bands in the spinal fluid) and (2) dissemination is space (symptoms and/or signs affecting two different pathways in the CNS) and (3) the exclusion of other possible diagnoses. It is clear that based on these criteria you don’t necessarily need to have visible, or specific, MRI lesions to make a diagnosis of MS. However, neurologists feel uncomfortable making a diagnosis of MS or CIS if there are no visible lesions on MRI. In other words from a practical and clinical perspective, MS has become a macroscopic or MRIscopic disease. Therein lies the rub. 


MS is a biological disease that is characterised pathologically by multifocal inflammatory lesions that cause demyelination and variable degrees of axonal loss. Please note I have dropped using the term white matter. MS is clearly both a white and grey matter disease with more than half the lesion burden in the largely MRI-lesion-invisible grey matter component (see study below). Even in the white matter where it is easier to see lesions the resolution of an MRI scan is down to about 3-4 mm. Many more lesions are found pathologically than what is seen on MRI or the naked eye. Therefore, particularly early on in the course of the disease, there will be a small number of people with MS with one or no lesions who have MS. 


A very small lesion in a strategic pathway can cause typical symptoms and signs, but when you investigate many of these patients with an MRI scan you see no obvious lesion in the expected area. This happens more often than not with a so-called internuclear ophthalmoplegia (INO); a very specific eye movement problem that presents with double-vision on looking to the left or right. This is an example of a microscopic lesion causing an MS attack. This is why we shouldn’t be using MRI to confirm, or make, a diagnosis of relapse in pwMS.

The study below that is rapidly becoming a citation classic in the field of MS, shows you with elegant infographics how large the lesion burden is in areas that are MRI invisible using our standard clinical sequences. 



Kutzelnigg et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12.



Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient’s clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

8 comments

  • But isn't the baseline lesion load predictive of outcome? Therefore someone with no lesions is likely to have benign MS.

    • Yes and no! Yes, because people with a high lesion load at baseline probably have had the disease a lot longer and have acquired more damage than someone with a low lesion load.

      No in the sense that a person with one or no lesions may be lucky in that one of their first lesions is symptomatic and bringing them to the attention of the medical profession. What we don't know is if this person will then go onto having very active disease or more indolent disease.

      What is missing is from a one off cross-sectional scan is the temporal profile, i.e. how quickly did the person acquire there baseline lesion load? Having Gd-enhancing lesions helps as it tells you that that person has at least been active in the last few weeks. This is why Gd-enhancement at baseline predicts a worse outcome because it is an activity marker.

      The good news if you have one or no lesions at baseline and you have MS is that provided you stop new lesions from forming you should have a greater chance of protecting that brain and spinal cord long term.

    • Is it possible for MS lesions to be mistaken for other things?

      I'm confident my first full blown relapse was in 2011, but wont bother with reasons why I'm sure. Importantly, whilst under the care of an orthaepedic surgeon, I had a MRI of my lumbar spine and the radiologist report states 'incidental note made of Tarlov cyst at S2'

      I've often wondered if this was a misdiagnosis and more generally whether others with MS will lack a prompt diagnosis for this reason?

  • If someone's MS continues to worsen following treatment with Cladribine, yet they have an MRI that shows no visible new lesions….what next? Would escalation treatment to Alemtuzumab or HSCT (or Ocrelizumab?) be permitted with no activity seen on scan?

    • I think my post on 'why you get worse despite being NEDA' goes a long way to answering this question.

      http://multiple-sclerosis-research.blogspot.com/2018/12/explaining-why-you-get-worse-despite.html

      I suppose your are asking that if you take a less effective DMT that only partially gets on top of your MS and converts it from being active, to smouldering MS, where the activity is below the threshold of the MRI would you have been better off taking the risks and going with the most effective DMT first-line?

      This is a very difficult question to answer, but all the data indicates that if you with the high-efficacy DMT first line you will do better on average than if you go the stepwise approach.

      However, I am not sure I would put cladribine on the lower rung of the efficacy scale. Based on the phase 3 data it is high efficacy DMT alongside fingolimod, but below ocrelizumab, natalizumab, alemtuzumab and HSCT.

    • Im not a dock but I would ask what is the problem with the worsening is it something that alemtzumab would get rid of or is it worsenng progrsammed from previous damage.

  • Is there a problem with the Academia model of MS?
    Research of pathology findings indicate that MS is possibly not as assumed. It seems that trigger events create lesions but lesions aren't specifically the cause of disabilities or accumulating disabilities.
    If pathology findings were investigated further and a finding of no lesion but nerve damage was the primary issue in MS and that trigger events caused by things such as diet, Lifestyle, stress and Environment it would change the pressure to use DMD's and spend lots of money doing so, with less quality of Life long-term as an outcome!
    I wonder why this paper wasn't an impact, a HUGE impact for Academia and a much needed positive for PwMS?
    https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30245-X/fulltext?fbclid=IwAR04EpnIZYAfsQSsRwFKqNJMabzSdgyx-DIMQlDZjGVWEpf4FuFoiqQCR9Q

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